[0001] The present invention is generally directed to an injection device, i.e. a drug delivery
device for selecting and dispensing a number of user variable doses of a medicament.
[0002] Pen type drug delivery devices have application where regular injection by persons
without formal medical training occurs. This may be increasingly common among patients
having diabetes where self-treatment enables such patients to conduct effective management
of their disease. In practice, such a drug delivery device allows a user to individually
select and dispense a number of user variable doses of a medicament. The present invention
is not directed to so called fixed dose devices which only allow dispensing of a predefined
dose without the possibility to increase or decrease the set dose.
[0003] There are basically two types of drug delivery devices: resettable devices (i.e.,
reusable) and non-resettable (i.e., disposable). For example, disposable pen delivery
devices are supplied as self-contained devices. Such self-contained devices do not
have removable pre-filled cartridges. Rather, the pre-filled cartridges may not be
removed and replaced from these devices without destroying the device itself. Consequently,
such disposable devices need not have a resettable dose setting mechanism. The present
invention is applicable for both types of devices, i.e. for disposable devices as
well as for reusable devices.
[0004] These types of pen delivery devices (so named because they often resemble an enlarged
fountain pen) generally comprise three primary elements: a cartridge section that
includes a cartridge often contained within a housing or holder; a needle assembly
connected to one end of the cartridge section; and a dosing section connected to the
other end of the cartridge section. A cartridge (often referred to as an ampoule)
typically includes a reservoir that is filled with a medication (e.g., insulin), a
movable rubber type bung or stopper located at one end of the cartridge reservoir,
and a top having a pierceable rubber seal located at the other, often necked-down,
end. A crimped annular metal band is typically used to hold the rubber seal in place.
While the cartridge housing may be typically made of plastic, cartridge reservoirs
have historically been made of glass.
[0005] The needle assembly is typically a replaceable double-ended needle assembly. Before
an injection, a replaceable double-ended needle assembly is attached to one end of
the cartridge assembly, a dose is set, and then the set dose is administered. Such
removable needle assemblies may be threaded onto, or pushed (i.e., snapped) onto the
pierceable seal end of the cartridge assembly.
[0006] The dosing section or dose setting mechanism is typically the portion of the pen
device that is used to set (select) a dose. During an injection, a spindle or piston
rod contained within the dose setting mechanism presses against the bung or stopper
of the cartridge. This force causes the medication contained within the cartridge
to be injected through an attached needle assembly. After an injection, as generally
recommended by most drug delivery device and/or needle assembly manufacturers and
suppliers, the needle assembly is removed and discarded.
[0007] A further differentiation of drug delivery device types refers to the drive mechanism:
There are devices which are manually driven, e.g. by a user applying a force to an
injection button, devices which are driven by a spring or the like and devices which
combine these two concepts, i.e. spring assisted devices which still require a user
to exert an injection force. The spring-type devices involve springs which are preloaded
and springs which are loaded by the user during dose selecting. Some stored-energy
devices use a combination of spring preload and additional energy provided by the
user, for example during dose setting.
[0008] An injection device comprising a housing with a receptacle for the product, a dosing
mechanism for setting a product dosage to be administered and for displaying the set
product dosage and a dispensing mechanism for dispensing the product is known e.g.
from
EP 2 814 547 B1 which discloses a manually driven device or from
WO 2014/117944 A1,
WO 2016/016184 A1 or
WO 2017/134131 A1 which disclose spring driven devices.
[0009] These known devices are provided with a display providing a visual feedback to a
user regarding the actually set dose size. The display of such devices typically involves
a number sleeve with a series of numbers corresponding to dose sizes being provided
on the outer surface of the number sleeve such that only the actually set dose is
visible through an opening or window in the housing. Especially for visually impaired
users, it may be desirable to get such information in a different manner, for example
on a separate display unit and/or such that the information may be stored.
[0010] It is an object of the present invention to provide an improved alternative to the
above solutions. Especially, it is an object of the present invention to provide an
injection device or a drug delivery device providing information to users regarding
the set dose size.
[0011] This object is solved by an injection device according to claim 1.
[0012] An injection device according to the present invention comprises a housing with a
receptacle for the product, a dosing mechanism for setting a product dosage to be
administered and for displaying the set product dosage and a dispensing mechanism
for dispensing the product. The dosing mechanism may comprise a dosing sleeve, e.g.
a number sleeve with numbers or symbols provided on its outer surface, which is rotatable
relative to the housing in a first direction for setting a product dosage and which
is rotatable relative to the housing in a second, opposite direction for correcting
or dispensing a product dosage. The dispensing mechanism of the device may comprise
a piston rod, which is moveable relative to the housing in a dispensing direction
in order to eject the set product dosage in a dispensing stroke corresponding to the
set product dosage, at least one sleeve, which is rotatable together with the dosing
sleeve relative to the housing in the second direction in order to eject the set product
dosage, and a clutch interposed between the dosing sleeve and the at least one sleeve
and rotatable with the dosing sleeve and/or the at least one sleeve. The present invention
is based on the idea that detecting movements of one or more component parts of the
injection device may be used to identify e.g. the actually set dose size and/or the
actual operation mode of the device. If a relative rotation between the clutch and
further component parts of the device occurs, e.g. in increments corresponding to
dose units, this relative rotation may be used to identify the actually set dose size.
For example, the device may further comprise at least a first detector for detecting
movement of the clutch relative to the dosing sleeve and/or the housing and/or the
at least one sleeve and a data processing unit connected to the first detector for
reading, storing, processing, transmitting and/or displaying signals received from
the first detector.
[0013] In an exemplary embodiment, the clutch may comprise first ratchet teeth for engaging
corresponding first teeth of the dosing sleeve such that relative incremental rotation
of the dosing sleeve with respect to the clutch in one direction, preferably the first
direction, is permitted while prevented in the opposite direction and second ratchet
teeth for engaging corresponding second teeth of the at least one sleeve such that
relative incremental rotation of the clutch with respect to the at least one sleeve
in one direction, preferably the second direction, is permitted while prevented in
the opposite direction. For example, the teeth may have the form of saw-teeth. The
clutch may have the form of a toothed ring, like the toothed ring provided interposed
between the dosing sleeve and the coupling sleeve in
EP 2 814 547 B1. Preferably, the first ratchet teeth and the second ratchet teeth are located on
the clutch facing in opposite axial directions. The incremental or stepwise rotation
may cause a clicking sound every time a pair of teeth re-engages thereby providing
an acoustical and/or tactile feedback to the user. Typically, one click corresponds
to one dose unit such that counting the number of clicks enables a user to identify
the set dose size.
[0014] The present invention is suitable for devices permitting dose setting and dispensing
the set dose as well as devices permitting dose setting, dose correcting and dispensing
the set dose. In this respect dose correcting is defined as reducing the size of a
set dose without dispensing the set dose. In other words, the term dose setting is
used indicating increasing the set dose, while the term dose correcting is used indicating
decreasing the set dose. Dose setting and dose correcting may include relative movement
of the first and/or second ratchet teeth. Thus, detecting the clicks produced during
dose setting and during dose correcting may be used to identify the resulting dose
size.
[0015] The first detector and the data processing unit are preferably adapted to detect
at least one of a rotational movement of the clutch, an angle of rotation the rotational
movement of the stop wheel and a direction of the rotational movement of the stop
wheel. Detecting start and stop of the rotational movement is indicative of the device
being used or not. Further, the angle of rotation is indicative of the size of a dose
which is selected and/or dispensed by the drug delivery device. The direction of the
rotational movement is indicative of the operation mode of the device, for example
if the clutch rotates in a first direction during dose setting and rotates in a second,
opposite direction during dose correction and/or dose dispensing. Summarizing, detecting
the movement of the clutch provides the required information for giving a feedback
to the user regarding the operation mode of the device. Further, the data processing
unit may be adapted to provide information about the dose size and/or amount of product
ejected from the device by the dispensing mechanism and/or the maximum dose set by
the dosing mechanism based on a rotation protocol containing data received from the
first detector. Either the first detector and/or a further detector are adapted to
detect the relative incremental rotation between the clutch and any further component
part of the device, e.g. the dosing sleeve and/or the housing and/or the at least
one sleeve, in the first direction and/or in the second direction.
[0016] As mentioned above, the relative incremental rotation between the clutch and the
dosing sleeve and/or the at least one sleeve may generate an acoustic feedback to
a user. Optionally, the first detector comprises at least one sensor for detecting
this acoustic feedback generated by relative incremental rotation between the clutch
and the dosing sleeve and/or the at least one sleeve. The sound generated during dose
setting may differ from the sound generated during dose correcting such that the sensor
may differentiate between dose setting and dose correcting. Other features may be
used in conjunction or as an alternative to identify whether a dose is set or corrected,
e.g. detecting the direction of rotation of the clutch and/or other component parts.
[0017] As an alternative or in addition to detecting an acoustical feedback, the first ratchet
teeth and/or the second ratchet teeth may be coated with a galvanic conductive material
and at least one of the first teeth and/or at least one of the second teeth are provided
with an elastic galvanic contact arranged for engaging with the galvanic conductive
material at each rotational increment. In other words, the first detector comprises
the elastic galvanic contact and the galvanic conductive material and each incremental
rotational movement provides an electric signal which may be counted by the data processing
unit. The resulting dose is e.g. calculated in counting the signals at the dialing
end, e.g. the interface between the dose sleeve and the clutch, and subtracting the
counted signals of the correcting end, e.g. the interface between the clutch and the
at least one sleeve.
[0018] According to a further embodiment, the first detector comprises at least one mechanical
switch which is provided between the first ratchet teeth and the first teeth and/or
between the second ratchet teeth and the second teeth and is arranged for detecting
engaging of the teeth at each rotational increment. Each switch engages with the respective
ratchet teeth at each incremental rotation and thus produces an electrical signal.
The dose calculation is done in a similar manner by the data processing unit as mentioned
above.
[0019] In a further embodiment, the first detector comprises at least one of a magnetic
sensor and an inductive sensor, e.g. suitable to detect the rotational position of
the dosing sleeve and/or the clutch. Data received from such a sensor may be analyzed
by an add-on device attached e.g. to a button or to the dosing sleeve. This method
may be used to calculate the set dose size taking into account a possible dose correction.
In other words, it is possible to detect the chosen dose by analyzing the rotational
positions of the dosing sleeve and the clutch.
[0020] The injection device may further comprise a second detector for detecting the relative
axial position of the clutch and the dosing sleeve. The data processing unit may be
connected to the second detector for reading, storing, processing, transmitting and/or
displaying signals received from the second detector. The additional detector may
be required to differentiate between dose setting, dose correcting and/or dose dispensing
be determining the relative axial position of the dosing sleeve relative to the clutch.
For example, the second detector comprises at least one of a magnetic sensor and an
inductive sensor.
[0021] Using a magnetic sensor or an inductive sensor may require that the clutch and/or
the dosing sleeve comprise a metallic material. For example, the dosing sleeve and/or
the clutch may be metallized, coated, printed or additives may be added to the component
parts, which typically mainly comprise a plastic material.
[0022] The data processing unit may be adapted to provide information about the device being
in its dose setting mode, its dose correction mode or its dose dispensing mode based
on data received from the first detector and the second detector. The data processing
unit may be provided within the housing of the injection device. For example, the
data processing unit and the first and second detector may be permanently provided
within the housing of the injection device. This includes embodiments in which the
data processing unit is connected to at least one of the first and second detector
by wire. As an alternative, the data processing unit may be detachable from the housing
and/or may be connected to at least one of the first and second detector by means
of a wireless connection. In other words, the data processing unit may be an add-on
device which may be attached to the housing and removed from the housing. Examples
for wireless communication between the data processing unit and at least one detector
may include communication via a near field communication (NFC) or via Bluetooth (BT).
[0023] Further, the data processing unit may be adapted to send data to and/or receive data
from a separate data processing and/or display device, e.g. portable handheld electronic
devices, via a near field communication (NFC) or via Bluetooth (BT). The data may
be queried after each use (injection) and read out or an add-on device could read,
process and store the data and send a rotation protocol via to another device for
further processing. The add-on device may alternatively transmit unprocessed data.
[0024] The at least one sleeve may be a component part which is in direct engagement with
the piston rod. For example, the at least one sleeve may be a drive sleeve which is
splined to the piston rod or which is in threaded engagement with the piston rod.
However, as an alternative, the at least one sleeve may be a component part which
is indirectly coupled to the piston rod, for example with a clutch or a transmission
element interposed between the at least one sleeve and the piston rod. The at least
one sleeve may be permanently coupled to the piston rod or may be selectively coupled
to the piston rod only in a certain mode of the injection device, for example during
dose dispensing. The injection device may comprise two sleeves, which are rotatable
relative to the housing in order to eject the set product dosage and which are rotationally
constrained relative to each other but displaceable relative to each other in the
dispensing direction. The second detector may detect actuation, i.e. rotation, of
one of these sleeves or of both sleeves.
[0025] The injection device typically comprises a cartridge containing a medicament. The
term "medicament", as used herein, means a pharmaceutical formulation containing at
least one pharmaceutically active compound,
wherein in one embodiment the pharmaceutically active compound has a molecular weight
up to 1500 Da and/or is a peptide, a proteine, a polysaccharide, a vaccine, a DNA,
a RNA, an enzyme, an antibody or a fragment thereof, a hormone or an oligonucleotide,
or a mixture of the above-mentioned pharmaceutically active compound,
wherein in a further embodiment the pharmaceutically active compound is useful for
the treatment and/or prophylaxis of diabetes mellitus or complications associated
with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such
as deep vein or pulmonary thromboembolism, acute coronary syndrome (ACS), angina,
myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis
and/or rheumatoid arthritis,
wherein in a further embodiment the pharmaceutically active compound comprises at
least one peptide for the treatment and/or prophylaxis of diabetes mellitus or complications
associated with diabetes mellitus such as diabetic retinopathy,
wherein in a further embodiment the pharmaceutically active compound comprises at
least one human insulin or a human insulin analogue or derivative, glucagon-like peptide
(GLP-1) or an analogue or derivative thereof, or exendin-3 or exendin-4 or an analogue
or derivative of exendin-3 or exendin-4.
[0026] Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) human insulin; Lys(B3),
Glu(B29) human insulin; Lys(B28), Pro(B29) human insulin; Asp(B28) human insulin;
human insulin, wherein proline in position B28 is replaced by Asp, Lys, Leu, Val or
Ala and wherein in position B29 Lys may be replaced by Pro; Ala(B26) human insulin;
Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin.
[0027] Insulin derivates are for example B29-N-myristoyl-des(B30) human insulin; B29-N-palmitoyl-des(B30)
human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl
LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30
human insulin; B30-N-palmitoyl- ThrB29LysB30 human insulin; B29-N-(N-palmitoyl-Y-glutamyl)-des(B30)
human insulin; B29-N-(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30)
human insulin and B29-N-(ω-carboxyheptadecanoyl) human insulin.
[0028] Exendin-4 for example means Exendin-4(1-39), a peptide of the sequence H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-lle-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.
[0029] Exendin-4 derivatives are for example selected from the following list of compounds:
H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,
H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2,
des Pro36 Exendin-4(1-39),
des Pro36 [Asp28] Exendin-4(1-39),
des Pro36 [IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or
des Pro36 [Asp28] Exendin-4(1-39),
des Pro36 [IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),
des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39),
wherein the group -Lys6-NH2 may be bound to the C-terminus of the Exendin-4 derivative;
or an Exendin-4 derivative of the sequence
des Pro36 Exendin-4(1-39)-Lys6-NH2 (AVE0010),
H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2,
des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,
H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,
H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2,
des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2,
H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,
H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25] Exendin-4(1-39)-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,
des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(S1-39)-(Lys)6-NH2,
H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2;
or a pharmaceutically acceptable salt or solvate of any one of the afore-mentioned
Exendin-4 derivative.
[0030] Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory
active peptides and their antagonists as listed in
Rote Liste, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin),
Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin,
Buserelin, Nafarelin, Goserelin.
[0031] A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid, a heparin,
a low molecular weight heparin or an ultra low molecular weight heparin or a derivative
thereof, or a sulphated, e.g. a poly-sulphated form of the above-mentioned polysaccharides,
and/or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically
acceptable salt of a poly-sulphated low molecular weight heparin is enoxaparin sodium.
[0032] Antibodies are globular plasma proteins (-150 kDa) that are also known as immunoglobulins
which share a basic structure. As they have sugar chains added to amino acid residues,
they are glycoproteins. The basic functional unit of each antibody is an immunoglobulin
(Ig) monomer (containing only one Ig unit); secreted antibodies can also be dimeric
with two Ig units as with IgA, tetrameric with four Ig units like teleost fish IgM,
or pentameric with five Ig units, like mammalian IgM.
[0033] The Ig monomer is a "Y"-shaped molecule that consists of four polypeptide chains;
two identical heavy chains and two identical light chains connected by disulfide bonds
between cysteine residues. Each heavy chain is about 440 amino acids long; each light
chain is about 220 amino acids long. Heavy and light chains each contain intrachain
disulfide bonds which stabilize their folding. Each chain is composed of structural
domains called Ig domains. These domains contain about 70-110 amino acids and are
classified into different categories (for example, variable or V, and constant or
C) according to their size and function. They have a characteristic immunoglobulin
fold in which two β sheets create a "sandwich" shape, held together by interactions
between conserved cysteines and other charged amino acids.
[0034] There are five types of mammalian Ig heavy chain denoted by α, δ, ε, γ, and µ. The
type of heavy chain present defines the isotype of antibody; these chains are found
in IgA, IgD, IgE, IgG, and IgM antibodies, respectively.
[0035] Distinct heavy chains differ in size and composition; α and γ contain approximately
450 amino acids and δ approximately 500 amino acids, while µ and ε have approximately
550 amino acids. Each heavy chain has two regions, the constant region (CH) and the
variable region (VH). In one species, the constant region is essentially identical
in all antibodies of the same isotype, but differs in antibodies of different isotypes.
Heavy chains γ, α and δ have a constant region composed of three tandem Ig domains,
and a hinge region for added flexibility; heavy chains µ and ε have a constant region
composed of four immunoglobulin domains. The variable region of the heavy chain differs
in antibodies produced by different B cells, but is the same for all antibodies produced
by a single B cell or B cell clone. The variable region of each heavy chain is approximately
110 amino acids long and is composed of a single Ig domain.
[0036] In mammals, there are two types of immunoglobulin light chain denoted by λ and κ.
A light chain has two successive domains: one constant domain (CL) and one variable
domain (VL). The approximate length of a light chain is 211 to 217 amino acids. Each
antibody contains two light chains that are always identical; only one type of light
chain, κ or λ, is present per antibody in mammals.
[0037] Although the general structure of all antibodies is very similar, the unique property
of a given antibody is determined by the variable (V) regions, as detailed above.
More specifically, variable loops, three each the light (VL) and three on the heavy
(VH) chain, are responsible for binding to the antigen, i.e. for its antigen specificity.
These loops are referred to as the Complementarity Determining Regions (CDRs). Because
CDRs from both VH and VL domains contribute to the antigen-binding site, it is the
combination of the heavy and the light chains, and not either alone, that determines
the final antigen specificity.
[0038] An "antibody fragment" contains at least one antigen binding fragment as defined
above, and exhibits essentially the same function and specificity as the complete
antibody of which the fragment is derived from. Limited proteolytic digestion with
papain cleaves the Ig prototype into three fragments. Two identical amino terminal
fragments, each containing one entire L chain and about half an H chain, are the antigen
binding fragments (Fab). The third fragment, similar in size but containing the carboxyl
terminal half of both heavy chains with their interchain disulfide bond, is the crystalizable
fragment (Fc). The Fc contains carbohydrates, complement-binding, and FcR-binding
sites. Limited pepsin digestion yields a single F(ab')2 fragment containing both Fab
pieces and the hinge region, including the H-H interchain disulfide bond. F(ab')2
is divalent for antigen binding. The disulfide bond of F(ab')2 may be cleaved in order
to obtain Fab'. Moreover, the variable regions of the heavy and light chains can be
fused together to form a single chain variable fragment (scFv).
[0039] Pharmaceutically acceptable salts are for example acid addition salts and basic salts.
Acid addition salts are e.g. HCI or HBr salts. Basic salts are e.g. salts having a
cation selected from alkali or alkaline, e.g. Na+, or K+, or Ca2+, or an ammonium
ion N+(R1)(R2)(R3)(R4), wherein R1 to R4 independently of each other mean: hydrogen,
an optionally substituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenyl
group, an optionally substituted C6-C10-aryl group, or an optionally substituted C6-C10-heteroaryl
group. Further examples of pharmaceutically acceptable salts are described in "
Remington's Pharmaceutical Sciences" 17. ed. Alfonso R. Gennaro (Ed.), Mark Publishing
Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia of Pharmaceutical Technology.
[0040] Pharmaceutically acceptable solvates are for example hydrates.
[0041] Non-limiting, exemplary embodiments of the invention will now be described with reference
to the accompanying drawings, in which:
- Figure 1
- shows an exploded view of the individual parts of an embodiment of an injection device
according to the invention;
- Figure 2
- shows a sectional view of a detail of the embodiment of Figure 1;
- Figures 3a-3c
- show component parts of the injection device of Figure 1; and
- Figure 4
- schematically shows a data processing unit together with sensors.
[0042] Figure 1 shows an exploded view of the individual parts of an embodiment of an injection
device according to the invention. This embodiment is designed as a so-called single-use
pen. That is to say, the injection device is issued to the user fully assembled, i.e.,
with product to be administered.
[0043] The typical course of the injection process may be as follows: the user removes the
protective cap 1 from the injection device and mounts an injection needle (not shown)
on the needle holder 2a of a receptacle 2. Now the dosage can be adjusted via the
rotary knob 11a. For this purpose, the rotary knob 11a is turned so that the dosing
sleeve 50, which forms a dosing mechanism or is part of a dosing mechanism, is screwed
out of the injection device. The dosing sleeve 50 is screwed out of the injection
device until the desired dosage is displayed in the window of the threaded sleeve
9. If an excessively high dosage is inadvertently set, the dosage can be corrected
by turning the rotary knob in the opposite direction, whereby the dosing sleeve 50
is screwed back into the housing. The dosing device limits the maximum adjustable
dosage to a predetermined value. If there is an attempt to screw the dosing sleeve
out of the housing past this value, a radial limit stop on the dosing sleeve 50 and
a counter-limit stop on the threaded sleeve 9 prevent further rotation by mutual interaction.
During the dosing and correction movements, the dosing sleeve 50 rotates relative
to the coupling sleeve 40. The coupling sleeve 40 is held rotationally fixedly in
a form fit or friction fit against the housing 5 by a reverse rotation lock, for example
by means of a toothed ring 7a rotationally fixed to the threaded nut 7 and biased
axially towards a corresponding set of ratchet teeth on an inner surface of the housing
5 by means of a spring 7b. This ratchet between the housing 5 and the threaded nut
7 may form a clicker generating an audible and/or tactile feedback during dose dispensing
as the teeth of ring 7a slip over the corresponding teeth of housing 5.
[0044] The coupling sleeve 40 is permanently rotationally locked to the axially stationary
threaded nut 7 by splines permitting relative axial movement between the coupling
sleeve 40 which is axially entrained by the dosing sleeve 50 and the stationary threaded
nut 7. The threaded nut 7 may be retained in the housing 5 by means of an insert 6
holding the threaded nut 7 against the bias of spring 7b. A clutch 60 is shown in
Figure 1 as a toothed ring which is interposed between rotary knob 11a and a flange
on coupling sleeve 40 such that relative rotation of the dosing sleeve 50 and the
coupling sleeve 40 is permitted during dose setting. Figures 2, 3a, 3b and 3c show
in detail that the clutch is provided with first ratchet teeth 61 on an end facing
towards corresponding first teeth 51 of the dosing sleeve 50 and is provided with
second ratchet teeth 62 on an opposite end facing towards corresponding second teeth
41 of the coupling sleeve 40.
[0045] The ratchet teeth interface 61, 51 between the dosing sleeve 50 and the clutch 60
is designed such that rotation of the dosing sleeve 50 in a first direction, e.g.
during dose setting, is permitted relative to the stationary clutch 60 with teeth
51, 61 slipping over each other and re-engaging in rotational increments. Due to the
saw-tooth like design of the teeth 51, 61 relative rotation of the dosing sleeve 50
and the clutch 60 in the opposite direction is prevented. The ratchet teeth interface
62, 41 between the coupling sleeve 40 and the clutch 60 is designed such that rotation
of the clutch 60 in a second direction, e.g. during dose correcting, is permitted
relative to the stationary coupling sleeve 40 with teeth 41, 62 slipping over each
other and re-engaging in rotational increments. Due to the saw-tooth like design of
the teeth 41, 62 relative rotation of the coupling sleeve 40 and the clutch 60 in
the opposite direction is prevented. Spring 13 keeps the ratchet interfaces 51, 61
and 41, 62 in contact but allows axial displacement of the clutch 60 and/or the coupling
sleeve 40 against the bias of spring 13 to allow slipping of the interfaces as described
above.
[0046] In the embodiments depicted in the Figures, multiple teeth 61, 62, 51 and 41 are
shown. However, the function of the injection device would be the same if with the
clutch 60 having multiple first ratchet teeth 61 at least one tooth 51 would be provided
on the dosing sleeve 50 and vice versa. In the same way, multiple second ratchet teeth
62 may interact with at least one tooth 41 and vice versa. While the torque transmitted
by an interface having multiple engaging teeth may be increased compared with only
a single pair of teeth engaging, providing only one or only few teeth on one of the
component parts may have advantages when providing a sensor in or on this component
part.
[0047] If the desired dosage has been set, the injection needle can be inserted at the intended
position on the body of the user. Then the user pushes the ejection button 14 in the
distal axial direction against the bias of spring 13 which is interposed between button
14 and coupling sleeve 40. This axial movement blocks a relative rotation between
the coupling sleeve 40 and the dosing sleeve 50 by means of the toothed ring of clutch
60, i.e. the coupling sleeve 40 and the dosing sleeve 50 are rotationally constrained
via the clutch 60. In case of further pressure in the distal axial direction, the
dosing sleeve begins to move back into the housing in a screwing motion. Because of
the established rotational lock between the dosing sleeve 50 and the coupling sleeve
40, the coupling sleeve 40 carries out the same movement as the dosing sleeve 50.
Because the coupling sleeve 40 is permanently rotationally locked to the axially stationary
threaded nut 7, the rotational movement of the dosing sleeve 50 is transmitted to
the threaded nut 7. No axial forces are transmitted to the threaded nut 7, because
the coupling sleeve 40 is mounted axially movably on the threaded nut 7. Thus, the
rotating threaded nut 7 produces an axial movement of the threaded piston rod 8 in
the distal direction, wherein the latter is guided axially and locked rotationally
in the housing 5 by means of splines 8a and is in threaded engagement with threaded
nut 7 by means of an external thread 8g. The flange 4 acts on the plug of the cartridge
3 and pushes it, corresponding to the displacement of the threaded piston rod 8 in
the distal direction as well, wherein the previously set dosage can be ejected or
administered. At the end of the administration, when the dosing sleeve has been completely
screwed back into the housing, radial stops on the dosing sleeve 50 and the threaded
sleeve 9 prevent further ejection and overrotation of the dosing device.
[0048] The embodiment of Figure 1 shows an optional limiting device which ensures that the
most recently set dosage can be completely ejected or injected. For this purpose,
the dosing sleeve 50 has a coaxially applied inner toothing and the coupling sleeve
40 has a lateral cutout in which the stop wheel 30 is inserted. The function of the
limiting device is described in
EP 2 814 547 B1 in more detail.
[0049] The embodiment of Figure 1 further shows a data processing unit 20 connected to a
first detector 21 and a second detector 22 for reading data responsive to signals
received from the first and second detectors 21, 22. The data processing unit 20 is
depicted as a component part being disposed on the outer surface of the housing 5.
It may be permanently attached to the housing 5 or may be an integral part thereof
or may be a separate, detachable unit. The data processing unit 20 may comprise a
power supply and a PCB suitable for e.g. data processing, data storing and/or display
of information.
[0050] The first detector 21 is disposed on the clutch 60. In more detail the first detector
21 may comprise a coating on the ratchet teeth 61, 62 of the clutch. For example,
the ratchet teeth 61, 62 are coated with a galvanic conductive material and an, e.g.
elastically deformable, galvanic contact is arranged on first teeth 51 and/or second
teeth 41 to engage with the galvanic conductive material. Thus, every time the teeth
51, 61 or 62, 41 re-engage an electric signal may be generated or transmitted.
[0051] Instead of the first detector 21 being provided at least partially on the clutch
60, the first detector 21 may be provided on the dosing sleeve 50. For example, the
first detector 21 may be a magnetic rotation encoder (quadrature), a vibrating structure
microelectromechanical systems (MEMS) gyroscope or a combination of an MEMS gyroscope
and an accelerometer. These small size devices may be easibily integrated into the
dosing sleeve 50. Generally, gyroscopes measure rotational motion. MEMS (microelectromechanical
system) gyroscopes are small, inexpensive sensors that measure angular velocity. The
units of angular velocity are measured in degrees per second (°/s) or revolutions
per second (RPS). Hence, when determining the duration of the measurement the rotation
angle can be determined that provides information about the dose size.
[0052] The optional second detector 22 is disposed in or on the housing 5 at a position
suitable for detecting axial movement of the clutch 60. As the clutch 60 is axially
entrained when the dosing sleeve 50 moves axially with respect to the housing 5 the
second detector 22 may be arranged on the dosing sleeve 50. If the first detector
21 is provided on the dosing sleeve 50, the first and second detectors 21, 22 may
be integrated into a single detector unit.
[0053] Figure 4 shows the first detector 21 with two sensors 21a and 21b located on respective
sides of clutch 60 and connected to the data processing unit 20. The processing of
the signals from the sensors in the data processing unit 20 is schematically indicated
in Figure 4.
[0054] The feature of a data processing unit 20 using the signals of a first detector 21
and, optionally, a second detector 22 for counting the size of the set dose may be
applied to other drug delivery devices having a component part, like a sleeve, wheel
or ring, performing a certain axial and/or rotational movement only during dose setting
and a different movement during dose correcting. Examples for devices into which the
data processing unit 20 with the first detector 21 and the second detector 22 may
be implemented are disclosed in
WO 2014/117944 A1, in
WO 2016/016184 A1, in
WO 2017/134131 A1 or in
WO 2016/001304 A1.
Reference Numerals
[0055]
- 1
- cap
- 2
- receptacle
- 2a
- needle holder
- 3
- cartridge
- 4
- flange
- 5
- housing
- 6
- insert
- 7
- threaded nut
- 7a
- toothed ring
- 7b
- spring
- 8
- piston rod
- 8a
- spline
- 8b
- thread
- 9
- threaded sleeve
- 11a
- rotary knob
- 13
- spring
- 14
- button
- 20
- data processing unit
- 21
- first detector
- 21a
- sensor
- 21b
- sensor
- 22
- second detector
- 30
- stop wheel
- 40
- coupling sleeve
- 41
- second teeth
- 50
- dosing sleeve
- 51
- first teeth
- 60
- clutch
- 61
- first ratchet teeth
- 62
- second ratchet teeth
1. An injection device comprising a housing (5) with a receptacle (2) for the product,
a dosing mechanism for setting a product dosage to be administered and for displaying
the set product dosage, the dosing mechanism comprising a dosing sleeve (50) which
is rotatable relative to the housing (5) in a first direction for setting a product
dosage and which is rotatable relative to the housing (5) in a second, opposite direction
for correcting or dispensing a product dosage, and a dispensing mechanism for dispensing
the product, the dispensing mechanism comprising a piston rod (8), which is moveable
relative to the housing (5) in a dispensing direction in order to eject the set product
dosage in a dispensing stroke corresponding to the set product dosage, at least one
sleeve (7; 40), which is rotatable together with the dosing sleeve (50) relative to
the housing (5) in the second direction in order to eject the set product dosage,
and a clutch (60) interposed between the dosing sleeve (50) and the at least one sleeve
(7; 40) and rotatable with the dosing sleeve (50) and/or the at least one sleeve (7;
40),
characterized in that the device further comprises at least a first detector (21) for detecting movement
of the clutch (60) relative to the dosing sleeve (50) and/or the housing (5) and/or
the at least one sleeve (7; 40) and a data processing unit (20) connected to the first
detector (21) for reading, storing, processing, transmitting and/or displaying signals
received from the first detector (21).
2. The injection device according to claim 1, wherein the clutch (60) comprises first
ratchet teeth (61) for engaging corresponding first teeth (51) of the dosing sleeve
(50) such that relative incremental rotation of the dosing sleeve (50) with respect
to the clutch (60) in one direction, preferably the first direction, is permitted
while prevented in the opposite direction and second ratchet teeth (62) for engaging
corresponding second teeth (41) of the at least one sleeve (7; 40) such that relative
incremental rotation of the clutch (60) with respect to the at least one sleeve (7;
40) in one direction, preferably the second direction, is permitted while prevented
in the opposite direction.
3. The injection device according to claim 1 or 2, wherein the first detector (21) and
the data processing unit (20) are adapted to detect at least one of a rotational movement
of the clutch (60), an angle of rotation the rotational movement of the clutch (60)
and a direction of the rotational movement of the clutch (60).
4. The injection device according to any one of the preceding claims, wherein the data
processing unit (20) is adapted to provide information about the dose size and/or
amount of product ejected from the device by the dispensing mechanism and/or the maximum
dose set by the dosing mechanism based on a rotation protocol containing data received
from the first detector (21).
5. The injection device according to any one of claims 2 to 4, wherein the first detector
(21) and/or a further detector are adapted to detect the relative incremental rotation
between the clutch (60) and the dosing sleeve (50) and/or the housing (5) and/or the
at least one sleeve (7; 40) in the first direction and/or in the second direction.
6. The injection device according to any one of claims 2 to 5, wherein the relative incremental
rotation between the clutch (60) and the dosing sleeve (50) and/or the at least one
sleeve (7; 40) generates an acoustic feedback and/or wherein the first ratchet teeth
(61) and the second ratchet teeth (62) are located on the clutch (60) facing in opposite
axial directions.
7. The injection device according to any one of claims 2 to 6, wherein the first ratchet
teeth (61) and/or the second ratchet teeth (62) are coated with a galvanic conductive
material and at least one of the first teeth (51) and/or at least one of the second
teeth (41) are provided with an elastic galvanic contact arranged for engaging with
the galvanic conductive material at each rotational increment, wherein the first detector
(21) comprises the elastic galvanic contact and the galvanic conductive material.
8. The injection device according to any one of claims 2 to 6, wherein the first detector
(21) comprises at least one mechanical switch which is provided between the first
ratchet teeth (61) and the first teeth (51) and/or between the second ratchet teeth
(62) and the second teeth (41) and is arranged for detecting engaging of the teeth
(51, 61; 41, 62) at each rotational increment.
9. The injection device according to any one of the preceding claims, wherein the first
detector (21) comprises at least one of a magnetic sensor and an inductive sensor.
10. The injection device according to any one of the preceding claims, further comprising
a second detector (22) for detecting the relative axial position of the clutch (60)
and the dosing sleeve (50), wherein the data processing unit (20) is connected to
the second detector (22) for reading, storing, processing, transmitting and/or displaying
signals received from the second detector (22).
11. The injection device according to any one of claims 9 to 10, wherein the second detector
(22) comprises at least one of a magnetic sensor and an inductive sensor.
12. The injection device according to any one of claims 9 to 11, wherein the clutch (60)
and/or the dosing sleeve (50) comprise a metallic material.
13. The injection device according to any one of claims 10 to 12, wherein the data processing
unit (20) is adapted to provide information about the device being in its dose setting
mode, its dose correction mode or its dose dispensing mode based on data received
from the first detector (21) and the second detector (22).
14. The injection device according to any one of the preceding claims, wherein the data
processing unit (20) is a separate component part provided detachable from the housing
(5), or wherein the data processing unit (20) is located in or on the housing (5).
15. The injection device according to any one of the preceding claims further comprising
a cartridge containing a medicament.